“Biopharmaceutical product” is understood to mean a product obtained from biotechnology—culture media, cell cultures, buffer solutions, artificial nutrition liquids, or a pharmaceutical product or more generally a product intended for use in the medical field. “Biopharmaceutical device” is understood to mean a device intended to be used in a process in the biological or pharmaceutical field—measurement or control means, means for processing a biopharmaceutical product, containers or parts of containers, transfer or closure means. Such biopharmaceutical products or devices are of high added value and it is important to be certain of their integrity, particularly the absence of contamination.
For the purposes of storage, shipment, or the execution of a process of a physical, chemical or biological nature, it is conventional to place such biopharmaceutical products or devices in disposable pouches that are flexible, closed, fluid-tight, sterile, and of plastic material such as polyethylene or a complex that includes polyethylene. Such a pouch comprises means for introducing into its inside space and means for removing from its inside space the biopharmaceutical product or device, it being possible to bring these means to their open or closed state according to the moment and the requirements.
There are known pouches of this type in which the two main walls are directly joined to each other. Once expanded, such pouches have a limited volume and remain relatively thin, which is why they are often called “pillow” or “2D” pouches (D meaning dimensions). Also known are 3D pouches which have two main walls connected by and sealed to two side gussets which can be folded flat or unfolded and spread open; the volume can then be at least 50 liters, and up to 3,000 liters or more. Such 3D pouches are described in document WO00/04131 or sold under the brand FLEXEL® 3D.
To be able to receive and protect a biopharmaceutical product or device as defined above effectively, it is essential that the inside space of the pouch—herein referred to as the pouch stricto sensu—and its contents, if any, are preserved from any deterioration originating from outside the pouch stricto sensu, such as contamination. This quality is referred to herein as “fluid-tightness”. The pouch stricto sensu must therefore be fluid-tight or must at least present a degree of fluid-tightness considered to be satisfactory. Such a pouch stricto sensu is therefore designed and manufactured to have the required fluid-tightness. However, manufacturing defects in the pouch stricto sensu which affect its fluid-tightness cannot be ruled out. It is also possible for the fluid-tightness of an initially satisfactory pouch stricto sensu to be impacted after its production.
The fluid-tightness of the pouch stricto sensu is impacted once the pouch stricto sensu contains one or more passages through the envelope that it forms, including porousness, this or these passages having one or multiple outlets on the outer face of the pouch stricto sensu, including the welds between the component parts of the pouch stricto sensu in question.
Before using or considering the use of a pouch stricto sensu, it is therefore indispensable to be able to ensure that it has the required fluid-tightness. A pouch stricto sensu that has this fluid-tightness is said to be of satisfactory integrity and is suitable for receiving and protecting a biopharmaceutical product or device. A pouch stricto sensu that does not have this fluid-tightness is said to be of unsatisfactory integrity and, as it is unsuitable for receiving and protecting a biopharmaceutical product or device, must be set aside and not used.
Methods and devices are known for verifying the integrity of all pouches during production. Thus the ASTM International standard F 2095-01 which is entitled “Standard Test Methods for Pressure Decay Leak Test for Nonporous Flexible Packages With and Without Restraining Plates” more specifically concerns the pressure decay method. This method is considered in two modes of execution: with or without expansion restraining plates (for example the device known under the brand SARTOCHECK® 4). In all cases, such devices are complex and bulky, and are difficult to transport or use at the final location where the pouches are used.
Also, assuming the pouch is of satisfactory integrity when produced, an accidental loss or failure of integrity can occur after production and before final use of the pouch, for example during the storage, shipment, distribution, or delivery phases, or during the phase immediately preceding the use of the pouch. This risk is even greater for phases that are long (for example the storage phase may last several years) or that involve manipulating the pouch or placing it in contact with objects that could damage it. Such non-integrity cannot be detected by an integrity verification method performed at the pouch's point of manufacture, before the loss of integrity occurs.
Documents U.S. Pat. No. 6,892,567 and U.S. Pat. No. 6,196,056 describe methods and devices for determining the integrity of a package or compartment, based on sending a test gas through the package or the wall of the compartment. This device and the associated measurement instruments form a complex and bulky system.
Document US 2007/0220956 describes a method and device for detecting a leak in a bag intended for bioprocessing and containing a conductive fluid, placed in a rigid outer container, consisting of an electrically operated leak detector. Such a method and device have the same limits as mentioned above, except they only have applications in the case of a pouch filled with an electrically conductive fluid and the presence of a rigid outer container.
Document U.S. Pat. No. 4,098,577 describes a method and indicator for detecting the loss of integrity of a transparent package containing a product which is sealed when packaged. The package is filled with an artificial atmosphere such as carbon dioxide or nitrogen. A pH sensitive detector is placed in the package and is visible through it. The detector changes color if there is a loss of artificial atmosphere after a loss of integrity of the package. In the embodiments presented, the package is rigid, the product is a solid object, and the detector is kept separate from the product. This method is unsuitable for packaging intended to receive a fluid product that will be into contact with the detector. In addition, it does not describe or suggest that the detection occurs before the product is placed in the packaging, quite the opposite.
Document U.S. Pat. No. 4,813,541 describes a tamperproof package and method. The package comprises a first internal container, rigid and hermetically sealed, filled with a first atmosphere and containing a substance, and a second external container, rigid and hermetically sealed, in which is located—kept apart by spacers—the first container, the inner cavity of the second container external to the first container being filled with a second atmosphere at a different pressure from that of the first atmosphere, and detection means placed in the cavity and sensitive to a change in the second atmosphere due to a loss of integrity of the first container or second container. Document U.S. Pat. No. 4,813,541, which describes a very specific structure, does not suggest having the detection occur before the substance is placed in the first container.
Document WO 01/04624 describes a colorimetric system comprising a detector sensitive to carbon dioxide.
Document WO96/12659 describes a so-called tamperproof packaging that comprises an inner membrane delimiting an inner compartment which contains a first medium consisting of air, as well as an outer membrane delimiting an outer compartment which surrounds the inner compartment and contains a second medium consisting of carbon dioxide. An indicator tab, sensitive to the surrounding medium, is provided inside the outer compartment, and it can give an indication of a change in the first medium and in the second media.
Document U.S. Pat. No. 4,434,893 describes a package for receiving products comprising inner and outer containers. In one embodiment, the inner container and outer container have only one flexible wall, and these inner and outer containers are pressurized using a gas above atmospheric pressure in order to inflate their flexible walls. In another embodiment, the two walls of the inner and outer containers are flexible. The products—capsules, gelcaps, or the like—to be protected are inside the inner container, and the inner container is positioned at of the outer container so as to form a protection that prevents access to the products.
Document U.S. Pat. No. 4,436,203 describes a package comprising an inner enclosure of predefined size, loaded with a product and pressurized before being placed inside an outer enclosure. After its internal pressure is reduced to below the atmospheric pressure, said outer enclosure is closed. Thus, when one of the walls of the package is pierced, the consumer is alerted of the fact that the product may have been affected.
Document FR 2252 619 describes a device intended for use with a package that is normally closed with a hermetic seal. It comprises a detector arranged so that it is in communication with the interior of the package but is also visible from the outside. This detector contains a pH sensitive dye which has a first color at the normal atmospheric pH and a second color at a pH slightly greater than or less than the normal atmospheric pH.
Document FR-A-2822445 concerns a package for infectious samples, comprising a bag of fluid-tight plastic material intended to enclose a container containing said sample within a layer of absorbent cloth characterized by said fabric being dyed such that any trace of humidity modifies its initial color, the bag of plastic material being transparent.
Document U.S. Pat. No. 5,219,524 concerns a system for preserving an acid-containing article which is in contact with an alkaline substrate material and an artificial atmosphere which is substantially free of gaseous oxygen. The article, alkaline substrate material, and artificial atmosphere are hermetically sealed within a container, at least a portion of the container being at least partially transparent so as to permit viewing the article from outside the container.
The invention therefore has the aim of overcoming the problems mentioned above, and permitting the determination of the integrity or non-integrity of a pouch stricto sensu at any desired moment after its manufacture and at least immediately prior to its planned use, in a certain, easy, and rapid manner, without requiring a bulky or complex dedicated device, or difficult or delicate operations, and without requiring specialized personnel specially and exclusively dedicated to integrity verification, and without needing to perform positive testing on the pouch to ensure its integrity, its non-integrity being indicated automatically and therefore without requiring positive testing of each pouch when the pouch is one of a plurality of pouches.
To this effect, a first aspect of the invention relates to an integrity/non-integrity indicator pouch, intended for receiving and protecting a biopharmaceutical product or device, comprising:                a first, inner, envelope which is flexible, closed, fluid-tight, and of plastic material, comprising a wall delimiting a first space, forming a pouch stricto sensu intended to receive the biopharmaceutical product or device, comprising first introduction means and first extraction means for respectively introducing/extracting the product or device, said means being in the closed state,        a second, outer, envelope which is closed, fluid-tight, and of plastic material, comprising a wall delimiting a second space in which is located the first envelope/pouch stricto sensu, comprising second introduction means and second extraction means for respectively introducing/extracting the first envelope/pouch stricto sensu, said means being in the closed state, an intermediate space thus being arranged in the second space outside the first envelope/pouch stricto sensu,        spacing means placed between the wall and the wall, such that the inner face of the wall does not occlude any integrity-impacting opening on the outer face of the wall,        at least one tracer gas, located either in the first space or in the intermediate space, at a partial pressure that is different from that of the intermediate space or of the first space, respectively, introduced into the first space and/or the intermediate space by tracer gas introduction means, now in the closed state,        at least one continuous colorimetric detection layer for detecting the tracer gas, responding to the concentration of the tracer gas which reaches it by changing from a first color to a second and different color, being an integral part of a wall of the first envelope/pouch stricto sensu and/or of a wall of the second envelope and/or of the spacer means,        the arrangement of the walls of the first envelope/pouch stricto sensu and of the second envelope, the spacer means, the tracer gas, and the colorimetric detection layer, on the one hand, and the permeability or impermeability to the tracer gas of the colorimetric detection layer, and of the spacer means, on the other hand, being chosen so that the colorimetric detection layer cannot be reached by tracer gas located in the intermediate space or in the first space at a concentration beyond the transition value, when the first envelope/pouch stricto sensu is of satisfactory integrity, and so that the colorimetric detection layer is in any case reached by the tracer gas located in the intermediate space or in the first space at a concentration beyond the transition value, when the first envelope/pouch stricto sensu is of unsatisfactory integrity.        
Thus, if the colorimetric detection layer is identified as being of the first color, the first envelope/pouch stricto sensu is considered to be of satisfactory integrity and suitable for receiving and protecting the biopharmaceutical product or device, but if it is identified as being of the second color, it is considered to be of unsatisfactory integrity and unsuitable for receiving and protecting the biopharmaceutical product or device.
In some embodiments, the spacer means comprise at least one porous layer fully and functionally covering the outer face of the wall of the first envelope/pouch stricto sensu and/or the inner face of the wall of the second envelope and/or the face of the colorimetric detection layer facing the intermediate space; or the spacer means comprise at least one porous layer which either structurally covers the outer face of the wall of the first envelope/pouch stricto sensu and/or the inner face of the wall of the second envelope and/or the face of the colorimetric detection layer facing the intermediate space, or is placed within the intermediate space.
In some embodiments, either the tracer gas is in the first space at a higher partial pressure than in the intermediate space, and the colorimetric detection layer changes from the first color to the second color in response to the concentration of tracer gas which reaches it rising above a transition value, or the tracer gas is in the first space at a lower partial pressure than in the intermediate space, and the colorimetric detection layer changes from the first color to the second color in response to the concentration of tracer gas which reaches it falling below a transition value.
In a first family of embodiments, a colorimetric detection layer is permeable to the tracer gas and is an integral part of the wall of the first envelope/pouch stricto sensu, being located on the outer face and in the intermediate space, or located on the inner face and in the first space, or inserted within the wall, between its outer face and its inner face and between the first space and the intermediate space.
In a second family of embodiments, a colorimetric detection layer is an integral part of the wall of the second envelope, being either located on the inner face and in the intermediate space, or inserted within the wall, between the inner face and its outer face, the layer of the wall of the second envelope adjacent on one side to the colorimetric detection layer and on the other side to the inner face then being permeable to the tracer gas.
In a third family of embodiments, a colorimetric detection layer is an integral part of a porous layer of the spacer means which is either located near the outer face of the wall of the first envelope/pouch stricto sensu or is located near the inner face of the second envelope, or a colorimetric detection layer and a porous layer of the spacer means are structurally combined to form a single layer.
Where applicable, the embodiments of these different families may be combined.
Depending on the case, the first envelope/pouch stricto sensu is a 2D pouch, or a 3D pouch comprising two gussets. In the latter case, and according to one embodiment, the spacer means comprise at least one porous layer which fully and functionally, and structurally where necessary, covers the outer face of the interior of the gussets.
In some possible embodiments, the spacer means comprise at least one porous layer which fully and functionally, and structurally where necessary, covers the first introduction means and the first extraction means for respectively introducing/extracting the biopharmaceutical product or device and the tracer gas introduction means of the first envelope/pouch stricto sensu. Or, the spacer means comprise at least one porous layer of fabric, nonwoven fabric, PE, PP, PTFE.
In some possible embodiments, a tracer gas is chosen from among the group comprising oxygen, carbon dioxide, and helium.
In two possible embodiments, one among the first space or the intermediate space contains tracer gas and the other among the intermediate space or the first space does not contain or substantially does not contain tracer gas.
In one embodiment, the second envelope allows identifying from outside of itself whether the colorimetric detection layer is of the first color or the second color.
In one embodiment, the second envelope is flexible.
In one embodiment, the integrity/non-integrity indicator pouch additionally comprises an outer protective packaging which houses the second envelope within which the first envelope/pouch stricto sensu is located.
A second aspect of the invention relates to an integrity/non-integrity indicator pouch of satisfactory integrity, consisting of an integrity/non-integrity indicator pouch as described above where the colorimetric detection layer is of the first color.
A third aspect of the invention relates to a method for creating an integrity/non-integrity indicator pouch as described above, wherein:                one provides a first envelope/pouch stricto sensu, a second envelope in which the second introduction means for introducing the first envelope/pouch stricto sensu are in the open state, spacer means, the tracer gas, the colorimetric detection layer which is an integral part of a wall of the first envelope/pouch stricto sensu and/or of a wall of the second envelope and/or of the spacer means,        the first envelope/pouch stricto sensu is introduced into the second space of the second envelope via the second introduction means in the open state, the spacer means being placed between the wall and the wall such that the inner face of the wall does not occlude any integrity-impacting opening in the outer face of the wall,        the tracer gas is introduced into either the first space or the intermediate space, at a partial pressure that is different from that of the intermediate space or of the first space, respectively, via the tracer gas introduction means which are in the open state, then these introduction means are brought to the closed state,        the arrangement is chosen so that the colorimetric detection layer cannot be reached or conversely is necessarily reached by the tracer gas, as required, and the permeability or impermeability to the tracer gas of the colorimetric detection layer and of the spacer means is accordingly chosen so that the colorimetric detection layer is in fact reached by the tracer gas when such is necessary,        the first envelope/pouch stricto sensu and the second envelope being closed.        
A fourth aspect of the invention relates to a method for obtaining a pouch stricto sensu of satisfactory integrity and ready to receive and protect a biopharmaceutical product or device, wherein:                one provides an integrity/non-integrity indicator pouch as described above,        the colorimetric detection layer is identified as being of the first color or the second color,        if the colorimetric detection layer is of the first color:                    the second extraction means, with which the second envelope is equipped in order to extract the first envelope/pouch stricto sensu, are brought to the open state,            the first envelope/pouch stricto sensu is extracted from the second space of the second envelope,            and the first introduction means, with which the first envelope/pouch stricto sensu, considered to be of satisfactory integrity, is equipped in order to introduce the biopharmaceutical product or device, are brought to the open state in order to place the biopharmaceutical product or device within,                        whereas if the colorimetric detection layer is of the second color, the first envelope/pouch stricto sensu is considered to be of unsatisfactory integrity and is not used for placing a biopharmaceutical product or device within.        
A fifth aspect of the invention relates to a process for making use of a pouch stricto sensu, which when of satisfactory integrity is intended for receiving and protecting a biopharmaceutical product or device, said process comprising:                at a point of manufacture, initial operations consisting of manufacturing a pouch stricto sensu,        at a point of use, final operations consisting of using the pouch stricto sensu by placing the biopharmaceutical product or device within,        intermediate storage, shipping, and handling operations, at one or more locations,and comprising:        the creation by the method described above, at the point of manufacture, of an integrity/non-integrity indicator pouch comprising a first envelope/pouch stricto sensu,        the shipping of the integrity/non-integrity indicator pouch from the point of manufacture to the point of use, including storage and handling operations when there are such,        and, at least at the point of use and before extracting the first envelope/pouch stricto sensu from the second envelope in order to place the biopharmaceutical product or device within, the identification of whether the colorimetric detection layer is of the first color or the second color,        if the colorimetric detection layer is identified as being of the first color, the first envelope/pouch stricto sensu is considered to be of satisfactory integrity and is used for placing the biopharmaceutical product or device within in order to receive and protect it,        whereas if the colorimetric detection layer is identified as being of the second color, the first envelope/pouch stricto sensu is considered to be of unsatisfactory integrity and is not used for placing the biopharmaceutical product or device within.        
In one embodiment, the identification of whether the colorimetric detection layer is of the first color or the second color is done concurrently with the intermediate storage, shipping, or handling operations.
In one embodiment, the identification of whether the colorimetric detection layer is of the first color or the second color is done at the point of use immediately prior to extracting first envelope/pouch stricto sensu from the second envelope in order to place the biopharmaceutical product or device within.